Sequential and selective Buchwald-Hartwig amination reactions for the controlled functionalization of 6-bromo-2-chloroquinoline: synthesis of ligands for the Tec Src homology 3 domain.
Src homology 3 (SH3) domains are highly conserved protein-protein interaction domains that mediate important biological processes and are considered valuable targets for the development of therapeutic agents. In this paper, we report the preparation of a range of new 6-heterocyclic substituted 2-aminoquinolines using Buchwald-Hartwig chemistry. 6-Heterocyclic substitution of the 2-aminoquinoline has provided ligands with increased binding affinity for the SH3 domain relative to the lead compound, 2-aminoquinoline, that are the highest affinity ligands prepared to date. The key step in the synthesis of these compounds required a selective Buchwald-Hartwig amination of an aryl bromide in the presence of an activated heteroaryl chloride. The optimization of reaction conditions to achieve the selective amination is discussed and has allowed for cross-coupling with a range of cyclic amines. Introduction of the amino functionality of the 6-heterocyclic 2-aminoquinolines involved additional Buchwald-Hartwig chemistry utilizing lithium bis(trimethylsilyl)amide as an ammonia equivalent.
Smith
Jessica A
JA
Discipline of Chemistry, School of Chemistry and Physics, The University of Adelaide, Adelaide, South Australia 5005, Australia.
Jones
Rhiannon K
RK
Booker
Grant W
GW
Pyke
Simon M
SM
D000586:Amination; D000818:Animals; D001665:Binding Sites; D008024:Ligands; D051379:Mice; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014297:Trimethylsilyl Compounds / Q000737:chemistry; D018909:src Homology Domains
C534160:6-bromo-2-chloroquinoline; D008024:Ligands; D011804:Quinolines; D014297:Trimethylsilyl Compounds; C437125:lithium bis(trimethylsilyl)amide; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases